Targeting Menin: A New Frontier in Treating Refractory Leukemias

In November 2024, the FDA approved the first-in-class menin inhibitor revumenib (Revuforj; Syndax) for the treatment of patients with relapsed/ refractory leukemia with KMT2A translocations, including myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed phenotype acute leukemia (MPAL). The approval is a critical step in understanding epigenetic leukemia vulnerabilities.

Menin-Induced Epigenetic Deregulation

NPM1-mutated AML and AML, ALL, and MPAL harboring KMT2A or NUP98r demonstrate gene signatures resulting in HOX and MEIS1 family gene proliferative deregulation (Figure 1). Blockage in myeloid differentiation and leukemia transformation are immediate biological consequences linked to these molecular defects. KMT2Ar de novo and therapy-induced pediatric and adult leukemias encode MLL1 subunits, such as MLL-N and MLL-C, which are capable of interacting with chromatin.1 The menin-binding motif is highly preserved in all MLL fusion proteins and is considered a canonical cofactor for HOX gene transcription start sites/promoters.

Results of a preliminary safety and early efficacy analysis of revumenib demonstrated that 77.9% (n = 53/68) of KMT2Ar and NPM1-mutated (NPM1m) relapsed or refractory, previously heavily treated patients with AML developed any-grade treatment-related adverse effects (TRAEs).2 Any-grade QTc prolongation (52.9%), nausea (26.5%), and vomiting (16.2%) were frequently observed. With a median time to onset of 18 days, 16.2% of patients developed differentiation syndrome. The complication was linked to arthralgias, fever, leukocytosis, and pleural/pericardial effusion, and it was promptly resolved with the administration of steroids and hydroxyurea. The rate of complete remission (CR) or complete remission with a partial hematologic recovery (CR/CRh) was 30.0% (95%CI, 18.8%-43.2%) among evaluable patients with undetectable negative measurable residual disease (MRD), and the overall response rate (ORR) was 53.0%.

Interestingly, transcriptomic modifications induced by revumenib were examined by RNA sequencing of hemopoietic cells reconfirming preestablished menin inhibition mechanisms of action associated with downregulation of MEIS1, HOXA9, and PBX3.3 Preliminary data suggesting suppression of FLT3 expression indicated that revumenib’s benefit potentially expands beyond canonical KMT2A and NPM1 genomic defects. The recommended phase 2 dose (RP2D) was established as 276 mg every 12 hours (160 mg/m2 if < 40 kg) without a strong CYP3A4 inhibitor and 163 mg every 12 hours (95 mg/m2 if < 40 kg) for those on a strong CYP3A4 inhibitor.

Phase 2 Trial, FDA Approval, and Novel Trial Design

The pivotal phase 2 AUGMENT-101 trial (NCT04065399) evaluated revumenib as monotherapy in patients with relapsed/refractory KMT2Ar AML or ALL. Ninety-seven pediatric and adult patients were included. The median age was 37.0 years (range, 1.3-75.0). At the time of enrollment, 43.6% of patients had received 3 or more anti-AML therapies. The most frequent TRAEs were nausea, differentiation syndrome, and QTc prolongation, which were observed in 27.7%, 26.6%, and 23.4 % of patients, respectively. Grade 3 or higher differentiation syndrome was observed in 16% of patients. In 57 patients included for efficacy analysis, the composite CR/CRh rate was 22.8%, surpassing the prespecified protocol null hypothesis of 10% (1-sided P=.0036); 70% of cases achieved MRD negativity.3 The median CR/CRh duration was 6.2 months (95% CI, 2.7-not estimable). Data demonstrated an unprecedented ORR of 63.2% for the single agent. Among 36 pediatric patients, CR/CRh rate was 23%, with 63% of patients achieving MRD negativity; the ORR was 46%. Fourteen (38.9%) patients who achieved a response had received allografting.

These remarkable results positioned revumenib as a breakthrough for patients with relapsed/refractory acute leukemia harboring KMT2A translocation, a genomic defect historically associated with dismal outcomes. Additionally, AUGMENT-101’s clinical and biologic data prompted revumenib’s investigation in combination with intense chemotherapy and other targeted therapies (Table 1).4-8

Promising results for a “total oral therapy” regimen, including revumenib, were reported during the 66th American Society of Hematology Meeting and Exposition in December 2024.9 The phase 1/2 SAVE trial (NCT05360160) demonstrated an ORR of 82% (n=27/33). The most frequent TRAEs included QTc prolongation, febrile neutropenia, and nausea. Noticeably, early introduction of BCL-2 inhibitor and oral decitabine/cedazuridine substantially mitigated the risk of DS previously observed in the AUGMENT-101 trial (≥ grade 3 differentiation syndrome, 3% in SAVE). A subset of KMT2Ar leukemias present with hyperleukocytosis, suggesting that cytoreductive therapy in combination with a menin inhibitor is an important biologic strategy.

AUGMENT-102 trial (NCT05326516), a phase 1 open-label study to investigate safety, tolerability, and preliminary antileukemic activity of revumenib in combination with chemotherapy in patients with relapsed/refractory leukemias harboring a KMT2Ar, NUP98r, or NPM1m is underway.10 In this trial, fludarabine plus cytarabine are administered in combination with revumenib. The composite CR rate was 55.6% (95% CI, 21.2%-86.3%) among patients treated at dose level 1 (n = 9) and 50.0% (95% CI,26.0%-74.0%) among patients treated at dose level 2 (n = 18) in a predominantly pediatric population with a median age of 6 years (range, 0.8-78.0). No differentiation syndrome was reported. In addition to the potential for differentiation syndrome mitigation, synergy from drug combination and limited exposure to anthracycline with known cardiotoxic effect are the appealing AUGMENT-102 trial results.

Further rationale supporting revumenib combination trials is based on the observation that terminal blast differentiation is immune transcriptomically associated with upregulation of CD11b and CD14 expression, and downregulation of FLT3 normally seen in fully differentiated effector myeloid cells.3 Additionally, HOXA/MEIS1 deregulation is not only observed in NPM1-mutated AML and subset of KMT2r leukemias but is also an oncogenic addiction for several other leukemias. We may continue to uncover an expanding list of KMT2A/ NPM1-like transcriptomic and/or methylome defects biologically relevant for menin inhibition.

Other Menin Inhibitors

Seven new and promising compounds that inhibit the HOX/MEIS1 transcriptional program are in clinical development. Among them, ziftomenib (KO-539; Kura Oncology) entered investigation in the phase 1/2 KOMET-001 trial (NCT04067336).11 The recommended RP2D of 600 mg was recently associated with a CR/CRh rate of 35%. At this dose level, differentiation syndrome was observed in 20% of patients. Remarkably, pharmacokinetic data did not demonstrate a major interaction between ziftomenib and CYP3A4 inhibitors. QTc prolongation was also not reported, differentiating it from other menin inhibitors in the class.

Another promising phase 1b trial (NCT05453903) is designed to address the safety and early efficacy of bleximenib (JNJ-75276617; Janssen) in combination with azacitidine (Vidaza) and venetoclax (Venclexta) in KMT2Ar- and NPM1-mutated AML.12 To date, 60 and 34 patients were included in safety and early efficacy analyses, respectively. Interestingly, no evidence of differentiation syndrome was reported, albeit most adverse effects were restricted to nausea and vomiting. The ORR was 79%.

Additional invesigational agents include DSP-5336 (Sumito Pharma), DS-1594 (Daiichi Sankyo), BN104 (BioNova Pharmaceuticals), and icovamenib (BMF-219; Biomea Fusion).

The oral covalent menin inhibitor icovamenib is being evaluated in the phase 1 COVALENT-101 trial (NCT05153330). Preclinical data demonstrated the drug's ability to destabilize menin interaction with KMT2A, modulate MYC expression, and regulate cell cycle pathways.13 Clinical efficacy was recently documented in adult post-allogeneic hematopoetic stem cell transplant patients with AML harboring NUP98-NSD1 fusion. CR was documented on day 1 of chemotherapy treatment cycle 3 with 0% blasts.14

The incorporation of menin inhibitors is central to improving the outcome of difficult-to-treat leukemias. However, there are barriers to overcome while targeting epigenetic codependencies. Importantly, that includes developing strategies that prevent clonal progression by acquisition of MEN1 and/or other epigenetic and nonepigenetic mutations. Monitoring KM2TA fusion and NPM1 mutational allele frequency may prove advantageous, but in AML, single-cell clonal tracking could facilitate better drug combinations and personalized therapies.

Leukemia Program Research at Tampa General Hospital Cancer Institute

Tampa General Hospital Cancer Institute's leukemia program is primed for robust clinical and laboratory research. Adult patients with KMT2Ar, NPM1m, or NUP98r AML have access to the phase 1 menin inhibitor clinical trial (NCT06313437) with revumenib in combination with cytarabine and daunorubicin (7+3) chemotherapy and midostaurin.

At our state-of-the-art biorepository, all samples from patients with AML, including those with the epigenetic mutations discussed, are collected and banked for ongoing and future collaborative research. Investigators have access to over 800 genomically diverse patients with AML in databases representing a multi-institutional effort to better dissect the acute leukemia genome. Sequential clonal inference, measurable residual disease, a large array of fusion proteins, and gene expression analysis have been incorporated into our databases.

Gustavo Rivero, MD, is the director of translational research for myeloid disorders at Tampa General Hospital Cancer Institute in Florida and an associate professor of hematology/oncology.

David Swoboda, MD, is the clinical director of leukemia at Tampa General Hospital Cancer Institute and an assistant professor at the University of South Florida Morsani College of Medicine in Tampa.

References

1. Cuglievan B, Kantarjian H, Rubnitz JE, et al. Menin inhibitors in pediatric acute leukemia: A comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community. Leukemia. 2024;38(10):2073-2084. doi:10.1038/s41375-024-02368-7
2. Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615(7954):920-924. doi:10.1038/s41586-023-05812-3
3. Issa GC, Cuglievan B, DiNardo C, et al. Early results of the phase I/II study investigating the all-oral combination of the menin inhibitor revumenib (SNDX-5613) with decitabine/cedazuridine (ASTX727) and venetoclax in acute myeloid leukemia (SAVE). Blood. 2023;142(suppl 1):58. doi:10.1182/blood-2023-182337
4. A phase I-II study Investigating the all oral combination of the menin inhibitor SNDX-5613 with decitabine/​cedazuridine (ASTX727) and venetoclax in acute myeloid leukemia (SAVE). ClinicalTrials.gov. Updated October 10, 2024. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT05360160
5. A study of revumenib in combination with chemotherapy in participants with R/​R acute leukemia. ClinicalTrials.gov. Updated August 13, 2024. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT05326516
6. Revumenib in combination with 7+3 + midostaurin in AML. ClinicalTrials.gov. Updated December 31, 2024. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT06313437
7. SNDX-5613 and gilteritinib for the treatment of relapsed or refractory FLT3-mutated acute myeloid leukemia and concurrent MLL-rearrangement or NPM1 mutation. ClinicalTrials.gov. Updated May 22, 2024. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT06222580
8. A phase II study of the menin inhibitor revumenib in leukemia associated with upregulation of HOX genes. ClinicalTrials.gov. Updated January 13, 2025. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT06229912
9. Issa GC, Cuglievan B, Daver N, et al. Phase I/II study of the all-oral combination of revumenib (SNDX-5613) with decitabine/cedazuridine (ASTX727) and venetoclax (SAVE) in R/R AML. Blood. 2024;144(suppl 1):216. doi:10.1182/blood-2024-204375
10. Neerav S, Guest E, Tasian SK. Safety and activity of revumenib in combination with fludarabine/cytarabine (FLA) in patients with relapsed/refractory acute leukemias. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P540.
11. Erba HP, Wang ES, Issa GC, et al. Activity, tolerability and resistance profile of the menin inhibitor ziftomenib in adults with relapsed or refractory NPM1-mutated AML. Presented at: 2023 European Hematology Association Congress; June 8-11, 2024; Frankfurt, Germany. Abstract LB2713.
12. Wei AH, Searle E, Aldoss I, et al. A phase 1b study of the menin-KMT2A inhibitor JNJ-75276617 in combination with venetoclax and azacitidine in relapsed/refractory acute myeloid leukemia with alterations in KMT2A or NPM1. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract S133.
13. Somanath P, Lu D, Balakrishnan M, Butler T. Covalent menin inhibitor, BMF-219, impacts key gene signatures and molecular pathways in chronic lymphocytic leukemia patient-derived models. Cancer Res. 2023;83(suppl 7):473. doi:10.1158/1538-7445.AM2023-473
14. Carraway HE, Nakitandwe J, Cacovean A, et al. Complete remission of NUP98 fusion-positive acute myeloid leukemia with the covalent menin inhibitor BMF-219, icovamenib. Haematologica. Published online December 5, 2024. doi:10.3324/haematol.2024.286537